This is a resubmission of grant application 1 R21 RR14221-01. The goal of this project is to provide new biodegradable, non- toxic macromolecular materials with minimized biological reactivity for advanced applications in pharmacology and bioengineering. The project addresses the fundamental problem of developing an "ideally biocompatible" material. This material must be non- recognizable by any biomolecules and receptors, non-vulnerable to "non-specific" interactions, stable in physiological conditions and, at the same time, metabolizable by cells (e.g., phagocytes). Presently, such materials are not available, and no rational nor other approaches to their development have been reported. In this study, we utilize a novel, "biomimetic" approach to developing biocompatible materials. The underlying mechanistic hypothesis of this work suggests that minimally bioreactive biodegradable polymers can be obtained via partial emulation of natural interface structures formed by oligo- and polycarbohydrates on cell surfaces and biomolecules (glycolipids, glycoproteins, etc.). Polymer structure should comprise the biologically inert structural fragments of interface carbohydrates, e.g., the acetal group (O-C-O) and the surrounding carbons, whereas the potentially biorecognizable structures formed by C1-C2-C3-C4 must be absent. Experimental samples of a lead biomimetic polyacetal, (poly[hydrohymethylethylene hydroxymethylformal]) (PHF), demonstrated excellent biocompatibility, extremely low toxicity and negligible interactions in vivo in a sensitive graft copolymer circulation test. The objective of this research is two-fold: (1) to further test the hypothesis of general bio- inertness of hydrophilic polyacetals; and (2) to initiate translation of the concept into a new biomedical technology on the basis of PHF. The expected outcome of this study includes: new knowledge on interaction of hydrophilic polyacetals with biological systems; new technologies for producing advanced materials for bioengineering, pharmacology, and biomedical research; new molecular tools for biomedical research; and a methodological basis for future preclinical studies.